This proposal deals with ongoing interest of this laboratory in glucagon physiology and in the extrapancreatic glucagon-like immunoreactive peptides described in animals and in man. Having discovered the presence of substantial quantities of a large glucagon-like material in the submaxillary glands of man and animals and having established preliminary evidence that these exocrine glands almost certainly also serve an endocrine function, the overall objectives are to further characterize this material and understand what role it plays in carbohydrate homeostasis. It is the purpose of this grant request to secure funds to: 1) Isolate rat submaxillary gland glucagon in sufficient quantity to allow a spectrum of physiologic studies to include its effect on hepatic glycogenolysis and gluconeogenesis, on insulin and growth hormone release, and on glucose tolerance; 2) Establish how glucagon secretion from these glands is regulated; 3) Determine the anatomical location of cells which synthesize and secrete this material; 4) Determine the phylogenetic and embryologic development of submaxillary gland glucagon; and, finally, 5) Determine the effects of removing these glands from young rats on subsequent growth and carbohydrate metabolism in both normal and experimentally diabetic rats. Antiserum will be raised to this material for additional studies, projected to begin after the period of this support. Work to date on this project has confirmed the presence of a large molecular weight glucagon-like immunoreactive substance in the submaxillary glands of several animal species. This material possesses biologic activity in terms of stimulating glycogenolysis from liver slices, competitively attaches to hepatocyte membrane receptors as does pancreatic glucagon, and rises significantly, in preliminary studies, following total pancreatectomy. In the course of these studies, it has been discovered that this material is largely androgen dependent, not appearing until puberty and declining to prepubertal levels following castration. A full study of the effects of this material on carbohydrate metabolism and in diabetes is still in progress.